This application relates to methods to supplement collagen and elastic tissues and thicken the dermis to reduce or eliminate the appearance of cellulite.
Human skin is a composite material of the epidermis and the dermis. The topmost part of the epidermis is the stratum corneum. This layer is the stiffest layer of the skin, as well as the one most affected by the surrounding environment. Below the stratum corneum is the internal portion of the epidermis. Below the epidermis, the topmost layer of the dermis is the papillary dermis, which is made of relatively loose connective tissues that define the micro-relief of the skin. The reticular dermis, disposed beneath the papillary dermis, is tight, connective tissue that is spatially organized. The reticular dermis is also associated with coarse wrinkles. At the bottom of the dermis lies the subcutaneous layer.
The principal functions of the skin include protection, excretion, secretion, absorption, thermoregulation, pigmentogenesis, accumulation, sensory perception, and regulation of immunological processes. These functions are detrimentally affected by the structural changes in the skin due to aging and excessive sun exposure. The physiological changes associated with skin aging include impairment of the barrier function and decreased turnover of epidermal cells, for example. [Cerimele, D., et al., Br. J. Dermatol., 122 Suppl. 35, p. 13-20 (April 1990)].
The mechanical properties of the skin, such as elasticity, are controlled by the density and geometry of the network of collagen and elastic fiber tissue therein. Damaged collagen and elastin lose their contractile properties, resulting in skin wrinkling and skin surface roughness. As the skin ages or becomes unhealthy, it acquires sags, stretch marks, bumps, bruises or wrinkles, it roughens, and it has reduced ability to synthesize Vitamin D. Aged skin also becomes thinner and has a flattened dermoepidermal interface because of the alterations in collagen, elastin, and glycosaminoglycans. [Fenske, N. A, and Lober, C. W., J. Am. Acad. Dermatol., 15:571-585 (October 1986); Montagna, W. and Carlisle, K., Journal of Investigative Dermatol., 73(1):47-53 (1979)].
Cellulite is a cosmetic/medical condition caused by defects in the skin that result in the skin having an xe2x80x9corange peelxe2x80x9d or xe2x80x9ccottage cheesexe2x80x9d effect. Cellulite is typically characterized by dermal deterioration due to a breakdown in blood vessel integrity and a loss of capillary networks in the dermal and subdermal levels of the skin. The vascular deterioration tends to decrease the dermal metabolism. This decreased metabolism hinders protein synthesis and repair processes, which results in dermal thinning. The condition is further characterized by fat cells becoming engorged with lipids, swelling, and clumping together, as well as excess fluid retention in the dermal and subdermal regions of the skin. Thus, individuals afflicted with cellulite tend to have a thicker subcutaneous fatty layer of skin. In the advanced stages of cellulite, reticular protein deposits called septa begin to form around the fatty deposits in the skin and occlude the fat cells. As the condition further progresses, hard nodules of fat cells and clumps of fat surrounded by septa form in the dermal region. This leads to the surface of the skin displaying considerable heterogeneity and being characterized as having a xe2x80x9ccottage cheesexe2x80x9d appearance. This appearance is most pronounced in overweight individuals. Individuals with cellulite also tend to have a thinner epidermis and dermis in the affected region, decreased firmness of the skin, and decreased rate of cell renewal.
The appearance of cellulite currently tends to be treated by administering xanthines, which include caffeine, theophylline, and aminophylline. Xanthines acts as a diuretic that removes water from the fat cells and thus reduces the size of the fat cells. The effect of xanthines, however, is temporary and the fat cells become rehydrated as soon as the individual replenishes the lost water.
A variety of vitamins and minerals have individually been administered to treat certain skin and other problems that occur when the patient has a deficiency of that vitamin or mineral. Vitamin A, for example, assists in the treatment of acne and to facilitate wound healing; vitamin C (ascorbic acid) assists in the prevention of skin bruising and wound healing; vitamin E is an antioxidant; and copper assists in the treatment of elastic tissue defects. [Neldner, K. H., Amer. Acad. Derm. Annl. Mtg., Wash. D.C., Dec. 6, 1993]. Topical use of vitamin C is also believed to ward off sun damage, reduce breakdown of connective tissues, and possibly promote collagen synthesis. [Dial, W., Medical World News, p. 12, March 1991]. Vitamin E is used topically as an anti-inflammatory agent, for enhancement of skin moisturization, for UV-ray protection of cells, and for retardation of premature skin aging.
Catechin-based preparations, including proanthanols and proanthocyanidins are powerful antioxidants. These compounds are found in flowers, plant leaves, and grape seeds, for example. [Lubell, A., Cosmetic Dermatol., 9(7):58 and 60 (July 1996)].
N-Acetylglucosamine and glucosamine have been examined for use in the prevention and treatment of degenerative joint diseases and cartilage loss, and found to increase the glycosaminoglycans present in the cartilage to restore cartilage. [See Grevenstein, J., et al., Acta Orthopaedia Belgica, 57(2):157-161 (1991); Setnikar, I., Drug Res., 36(4):720-733 (1986); Drovanti, A., et al, Clin. Therap., 3(4):1-6 (1980)]. Glucosamine has also been examined in connection with arthritis [See, e.g., Murray, M. T.] and oral and injected glucosamine have been reported to be useful for arthrosic patients. [Tapadinhas, M. J., et al., Pharmatherapeutica, 3(3):157-168 (1982); D""Ambrosio, E., et al., Pharmatherapeutica, 2(8):504-508 (1981)].
The metabolism of glycosaminoglycans under the influence of herbal and other anti-inflammatory agents has been examined by measuring glycosaminoglycans in the skin, liver, kidney, and spleen after administration of several compounds. [Reddy, G. K., et al., Biochem. Pharmacology, 38(20):3527-3534 (1989)].
In addition to their individual use to supplement a deficiency in a patient, various of the above ingredients have been combined to form pharmaceuticals designed to prevent and treat certain cellular, skin, and other conditions. For example, U.S. Pat. No. 3,773,930 discloses a low residue, dietary composition having at least one amino acid and a quantity of non-amino acid derived caloric material sufficient to obviate the diarrhea problem of straight amino acid compositions. A flavoring material may also be included to render the composition more palatable.
U.S. Pat. No. 4,285,964 discloses a salt of (+)-catechin formed by reacting (+)-catechin with at least a basic amino acid, such as L-lysine and L-arginine; and a hydrosoluble double salt formed from the reaction product of (+)-catechin with a basic amino-acid, such as L-lysine and L-arginine, and another inorganic or organic acid. The patent further discloses methods of treating degenerative diseases of the connective tissue by topically administering the composition.
U.S. Pat. No. 4,414,202 discloses a composition for the treatment of skin wounds with a buffered salt solution having a pH between 6 to 7.8 and administering a starch hydrolysate compound, and preferably including alphaketoglutaric acid or alphaketoglutarate salts. Optional additives to the composition include ascorbic acid or salts thereof, ferrous salts, and glycine, L-Proline, and L-Lysine.
U.S. Pat. No. 4,424,232 discloses a topical composition for the treatment of herpes simplex, cold sores, lesions, and other painful skin conditions including L-lysine, gibberellic acid, and urea in an inert carrier having water. The composition may also include L-ascorbic acid, as well as methyl paraben, propyl paraben, or mixtures thereof.
U.S. Pat. No. 4,647,453 discloses a method and composition for treatment of tissue degenerative inflammatory disease in animals and humans by oral administration of ascorbic acid, bioavailable calcium, a precursor or stimulant of epinephrine or nor-epinephrine of tyrosine or phenylalanine, and an anti-inflammatory substance selected from anti-inflammatory sugars, amino sugars and biocompatible acid addition salts thereof, and anti-inflammatory amino acids, to promote connective tissue regrowth.
U.S. Pat. No. 5,198,465 discloses a composition for treating precursor deficiencies in the synthesis of collagen with proline, glycine, lysine, vitamin C, and one or more compounds selected from xcex1-ketoglutaric acid, methionine, cysteine, cystine, valine, and pharmaceutically acceptable diluents and excipients.
U.S. Pat. Nos. 5,332,579 and 5,308,627 disclose a nutritional supplement to assist persons recovering from addiction by administering a variety of vitamins and minerals including enzyme activating substances such as magnesium and zinc; an enzyme co-factor that is a vitamin like various vitamin B complexes; an enzyme producer such as an amino acid like glutamic acid; an herbal antispasmodic substance like Valerian root; and vitamin C.
U.S. Pat. No. 5,415,875 discloses a method of suppressing formation of lipid peroxide and removing peroxide by applying to the skin a decomposed product of shell membrane and tocopherol and derivatives. Lysine, proline, Vitamin C, for examples, are listed among a vast genus of optional additives.
The above references, however, do not teach pharmaceutical compositions or methods for reducing or eliminating the appearance of cellulite. The present invention provides such a method. The method reduces or eliminates the appearance of cellulite by administering to a patient in need of treatment a composition that supplements collagen and elastic tissue in the skin and thickens the dermis.
The present invention relates to compositions for reducing or eliminating the appearance of cellulite in a patient. The composition includes a sugar compound that is converted to a glycosaminoglycan in the patient in an amount sufficient to thicken the skin, a primary antioxidant component in an amount sufficient to substantially inhibit the activity of collagenase and elastase, at least one amino acid component in an amount sufficient to assist in the thickening of the skin, and at least one transition metal component in an amount effective to bind collagen and elastic fibers and thicken the skin. In a preferred embodiment, the composition further includes at least one fat burner to reduce absorption of fat in the digestive tract or prevent the production of fat. In another preferred embodiment, the composition further includes at least one vascular dilator to improve blood supply to the skin.
The invention further relates to methods for reducing or eliminating the appearance of cellulite. The method involves administering to a patient in need of treatment a sugar compound that is converted to a glycosaminoglycan in the patient in an amount sufficient to thicken the skin, a primary antioxidant component in an amount sufficient to substantially inhibit the activity of collagenase and elastase in the skin, at least one amino acid component in an amount sufficient to assist in the thickening of the skin, and at least one transition metal component in an amount effective to bind collagen and elastic fibers and thicken skin, so as to modify the thickness of the skin to reduce or eliminate the appearance of cellulite.
The sugar, the primary antioxidant, at least one amino acid component, and at least one transition metal component may be administered sequentially, as well as simultaneously in the form of a single pharmaceutical composition, or in any combination thereof. The composition may be administered orally or topically. When the composition is administered orally it may be administered as a tablet or capsule having 1 mg to 2,000 mg of the composition. When the composition is administered topically it is preferably administered with one or more mono- or poly-hydroxy acids, a mixture thereof, or a pharmaceutically acceptable salt or ester thereof in an amount sufficient to exfoliate at least a portion of the skin. The mono- or poly-hydroxy acid may be tannic acid or salicylic acid.
In a preferred embodiment, the method further includes administering at least one fat burner in an amount sufficient to reduce absorption of fat in the digestive tract or prevent the production of fat. The sugar, the primary antioxidant, the at least one amino acid component, the at least one transition metal component, and the at least one fat burner may be administered sequentially, simultaneously as a pharmaceutical composition, or in any combination thereof, e.g., a composition of the first four components followed by the at least one fat burner.
In another preferred embodiment, the method further includes administering at least one vascular dilator in an amount sufficient to improve blood supply to the skin. The sugar, the primary antioxidant, the at least one amino acid component, the at least one transition metal component, and the at least one vascular dilator may be administered sequentially, simultaneously as a pharmaceutical composition, or in any combination thereof.
In another embodiment, the sugar, the primary antioxidant, the at least one amino acid component, the at least one transition metal component, and the at least one vascular dilator may be administered in conjunction with at least one fat burner to reduce absorption of fat in the digestive tract or prevent the production of fat.
Preferred fat burners include hydroxy citric acid, chitin, or a mixture thereof. When the fat burner is hydroxy citric acid, it is preferable to administer about 750 mg to 1500 mg of hydroxy citric acid. When the fat burner is chitin, it is preferable to administer from about 1000 mg to 2000 mg of chitin.
Preferred vascular dilators include extract of ginko biloba, ginsing, phenylalanine, or a mixture thereof. When the vascular dilator is extract of ginko biloba, it is preferable to administer from about 5 mg to 300 mg of extract of ginko biloba. When the vascular dilator is ginsing it is preferable to administer from about 100 mg to 200 mg of ginsing extract When the vascular dilator is phenylalanine it is preferable to administer from about 75 mg to 1500 mg of phenylalanine. A sufficient amount of vascular dilator can readily be determined by one of ordinary skill in the art.
Optionally the sugar, the primary antioxidant, the at least one amino acid component, the at least one transition metal component, and/or vascular dilator, and/or fat burner can be administered with from about 10 mg to 500 mg of chromium picolinate to facilitate entry of sugar into cells to improve metabolism of fats by the body.
A method for reducing or eliminating the appearance of cellulite has now been discovered. The method includes administering to a human in need of treatment therapeutically sufficient amounts of at least one sugar compound which is converted into glycosaminoglycans in the bloodstream, a primary antioxidant component, at least one amino acid component, and at least one transition metal component, so as to modify the thickness of the skin to reduce or eliminate the appearance of cellulite. Without wishing to be bound by theory, Applicant believes that a thicker dermis desirably reduces the appearance of cellulite that occurs when areas of the skin become thin. Improved compositions have also been discovered that are used in preferred methods. These compositions and methods preferably include a vascular dilator and/or a fat burner. Furthermore, the compositions and methods of the present invention result in stronger blood vessels. Skin and blood vessels are both connective tissues and thus, without wishing to be bound by theory, it is believed that the blood vessels are strengthened by the same process that leads to thickening of the skin.
The composition preferably contains at least one sugar compound, and more preferably just one sugar compound, present in about 5 to 50 weight percent, preferably about 10 to 40 weight percent, and more preferably about 15 to 30 weight percent of the composition. The primary antioxidant component is preferably present in an amount of about 5 to 50 weight percent, more preferably about 10 to 40 weight percent, and most preferably about 15 to 30 weight percent of the composition. The amino acid component is preferably present in about 8 to 60 weight percent, more preferably about 15 to 50 weight percent, most preferably about 20 to 40 weight percent of the composition. The transition metal component is preferably present in about 0.5 to 15 weight percent, more preferably present in about 2 to 12 weight percent, and most preferably present in about 5 to 10 weight percent of the composition.
The first component of the composition is any sugar compound that is converted to a glycosaminoglycan in the human bloodstream. Typically, this would be an N-acetylglucosamine compound, or a pharmaceutically acceptable salt or ester thereof. The N-acetylglucosamine component may be N-acetylglucosamine or any pharmaceutically acceptable salt or ester thereof, but more preferably is the N-acetylglucosamine only. This component must be present in sufficient quantity in the pharmaceutical composition to promote thickening of the dermis. Without wishing to be bound by theory it is believed that one mechanism by which glycosaminoglycans help thicken the skin is by improving the skins ability to absorb moisture. It is also believed that glycosaminoglycans are an important factor in assisting fibroblasts in producing collagen and elastic tissue. Thus, it can be advantageous to administer the composition in conjunction with a topically administered exfoliant that further improves the skin""s ability to absorb moisture by removing dead and dying skin cells from at least a portion of the skin. The N-acetylglucosamine is present in about 5 to 30 weight percent, preferably 8 to 27 weight percent, and more preferably 12 to 24 weight percent of the pharmaceutical composition. A unit dose of N-acetylglucosamine is typically about 40 mg to 250 mg, preferably about 60 to 200, and more preferably about 100 mg to 200 mg.
The pharmaceutical composition includes a primary antioxidant component, which typically includes a vitamin C source and preferably is ascorbic acid, or a pharmaceutically acceptable salt or ester thereof, and more preferably is ascorbyl palmitate, dipalmitate L-ascorbate, sodium L-ascorbate-2-sulfate, glucosamine ascorbate, or an ascorbic salt, such as sodium, potassium, or calcium ascorbate, or mixtures thereof. The antioxidant component inhibits collagenase and elastase, enzymes that break down collagen and elastic tissues. In addition, vitamin C also strengthens blood vessels. When oral formulations of the pharmaceutical composition are used, it is preferred that a non-acidic form of vitamin C be used to reduce the stomach irritation that may occur when using an acidic form. The vitamin C source is present in the pharmaceutical composition in about 5 to 50 weight percent, preferably about 7 to 40 weight percent, and more preferably about 10 to 25 weight percent. A unit dose when a vitamin C source is the primary antioxidant component is typically from about 40 mg to 400 mg, preferably about 60 mg to 300 mg, and more preferably about 80 mg to 150 mg. Vitamin C is also approved by the FDA and has wide consumer acceptance, so that it can be used in amounts as high as 10,000 mg, if desired.
The pharmaceutical composition also includes at least one amino acid to assist in thickening the skin. The amino acids assist in the thickening of the dermis, supplementing of collagen and elastic tissues and, consequently, reducing or eliminating the appearance of cellulite. Preferably two or more amino acids are used in combination. Either the L- or D-forms of amino acids are acceptable. Lysine or proline are the most preferred amino acids and they are advantageously used in combination. Cysteine, glycine, methionine or other amino acids can also be used, if desired. The amino acid(s) may be included in a soluble form such as the hydrochloride, i.e., L-Lysine hydrochloride. The amino acid(s) are present in an amount of about 2 to 25 weight percent each, preferably about 4 to 20 weight percent each, and more preferably about 6 to 15 weight percent each. A unit dose for each amino acid is typically about 35 mg to 200 mg each, preferably about 50 mg to 150 mg each, and more preferably about 70 mg to 120 mg in the pharmaceutical composition. Additional useful forms of amino acid include the following: a cysteine source, preferably N-acetyl cysteine, can be present in an amount of about 1 to 10 weight percent, preferably about 2 to 8 weight percent, and more preferably about 3 to 6 weight percent of the pharmaceutical composition. A methionine source, preferably L-selenomethionine, can be present in an amount of about 0.1 to 5 weight percent, preferably 0.2 to 3 weight percent, and more preferably 0.3 to 1 weight percent of the composition, wherein the selenium component is from about 0.1 to 3 weight percent of the methionine source.
One or more transition metal compounds are included in an amount effective to bind collagen and elastic tissue to rebuild the skin. Certain transition metal compounds also inhibit elastase, an enzyme that also breaks down collagen and elastic tissue. Preferred transition metals include zinc, manganese and copper, with combinations thereof being most preferred.
A zinc component can be included to assist in binding collagen and elastic fibers, which both assists in the rebuilding of skin. The zinc component may be any zinc compound or pharmaceutically acceptable salt thereof, but more preferably is a zinc complexed with an amino acid, and most preferably is zinc monomethionine, wherein the zinc is typically present in about 10 to 30 weight percent of the complex. The zinc component is present in about 1 to 10 weight percent, more preferably about 2 to 7 weight percent, and most preferably about 3 to 5 weight percent of the pharmaceutical composition.
A manganese component can also be included to assist in binding collagen and elastic fibers. The manganese component may be any manganese compound or pharmaceutically acceptable salt thereof, but more preferably is a manganese component which is at least partially complexed with a vitamin C source, and most preferably is manganese ascorbate or manganese ascorbic acid, wherein the manganese is typically present in about 5 to 20 weight percent of the complex. When complexed with vitamin C, this vitamin C source may be included in the overall percentage of vitamin C in the pharmaceutical composition. The manganese component is typically present in about 1 to 10 weight percent, more preferably about 2 to 7 weight percent, and most preferably about 2.5 to 4 weight percent of the pharmaceutical composition.
A copper component is preferably also included in the pharmaceutical composition, and may be any copper compound or pharmaceutically acceptable salt thereof, but preferably is copper sebacate, wherein the copper is typically present in about 5 to 20 weight percent of the copper sebacate. The copper component also inhibits elastase and is present in about 0.1 to 5 weight percent, preferably about 0.2 to 3 weight percent, and more preferably about 0.3 to 1 weight percent of the pharmaceutical composition. A unit dose of the copper component of the pharmaceutical composition may include about 1 mg to 40 mg, preferably about 2 mg to 25 mg, and more preferably about 2.5 mg to 10 mg of.
In another preferred form of the invention, the pharmaceutical composition further includes a catechin-based preparation, such as a proanthanol or proanthocyanidin, along with glucosamine or a pharmaceutically acceptable salt or ester thereof, and chondroitin or a pharmaceutically acceptable salt or ester thereof.
The catechin-based preparation, similar to vitamin C, inhibits elastase and collagenase, which is another enzyme that attacks elastic tissue and collagen. The catechin-based preparation is preferably a proanthanol or proanthocyanidin, more preferably a proanthocyanidin, and most preferably grape seed extract. These compounds are considered to be secondary antioxidants, because they are present in lesser amounts than the primary antioxidant. The catechin-based preparation is present in about 0.5 to 5 weight percent, more preferably about 0.6 to 3 weight percent, and most preferably about 0.7 to 2 weight percent of the pharmaceutical composition.
The glucosamine or a pharmaceutically acceptable salt or ester thereof, and the chondroitin or a pharmaceutically acceptable salt or ester thereof, are each present in about 3 to 17 weight percent, preferably about 4 to 12 weight percent each, and more preferably about 5 to 8 weight percent each of the pharmaceutical composition. The glucosamine component preferably is present as a sulfate or succinate, and more preferably is D-glucosamine sulfate, wherein the glucosamine is preferably present as about 60 to 90 weight percent of the salt. The glucosamine content of this component contributes to the formation of glycosoaminoglycans in the skin. The chondroitin component preferably is present as a sulfate or succinate, and more preferably is chondroitin sulfate, wherein the chondroitin is preferably present as about 65 to 95 weight percent of the salt.
In another preferred embodiment, the pharmaceutical composition includes at least one fruit extract, which provides antioxidants that are naturally present in the fruit extracts. Preferably, the fruit extract is obtained from apricots, apples, pears, peaches, pineapples, papayas, cherries, kiwis, tangerines, or oranges. Most preferably, the fruit extract is obtained from pomegranate. The fruit extract is preferably present in an amount of about 0.01 to 80 weight percent and more preferably in about 0.1 to 20 weight percent of the pharmaceutical composition. A preferred oral daily dose range of the fruit extract, when included in the composition, should be from about 0.01 mg to 2,000 mg; more preferably about 400 mg to 1,600 mg; and most preferably about 800 mg to 1,200 mg. In general, a preferred topical daily dosage range, in single or divided doses, should be from about 0.01 mg to 20,000 mg, more preferably about 2,000 mg to 16,000 mg and most preferably 6,000 mg to 10,000 mg of the fruit extract.
In a more preferred form, several optional additives are included in the pharmaceutical composition, such as a vitamin E source, a vitamin B3 source, quercetin powder, pyridoxal 5 phosphate-Co B6, and a vitamin A source. The vitamin E preferably is a sulfate or succinate vitamin E complex, and more preferably is D-alpha tocopheryl acid succinate. The vitamin E source is present in about 1 to 15 weight percent, preferably about 2 to 12 weight percent, and more preferably about 3 to 10 weight percent of the composition. In any event, no more than 1,500 IU should be ingested per day, as Vitamin E becomes toxic at higher doses. The vitamin B3 source preferably is niacinamide, and the source is present in about 0.5 to 15 weight percent, preferably about 1 to 12 weight percent, and more preferably about 1.5 to 10 weight percent of the composition. The vitamin A source preferably is vitamin A palmitate, and the source is present in about 0.1 to 5 weight percent, preferably 0.2 to 3 weight percent, and more preferably 0.3 to 1 weight percent of the composition. Vitamin A is toxic at high levels, such that no more than 400,000 IU should be cumulatively ingested per day for greater than six months. The quercetin powder is quercetin dihydrate, which is typically present in about 0.5 to 15 weight percent, preferably about 1 to 12 weight percent, and more preferably about 1.5 to 10 weight percent of the composition. The pyridoxal 5 phosphate-Co B6, also known as P-5-P monohydrate, is typically present in about 0.1 to 5 weight percent, preferably 0.2 to 3 weight percent, and more preferably 0.3 to 1 weight percent of the composition.
In another preferred form, the pharmaceutical composition also includes at least one vascular dilator or xe2x80x9cfat burner.xe2x80x9d
The vascular dilator may be administered in an amount sufficient to improve blood supply to the skin. Without wishing to be bound by theory, vascular dilators are also believed to strengthen blood vessels. Any suitable compound that improves blood supply to the skin available to one of ordinary skill in the art may be used. Vascular dilators include, but are not limited to, ginko biloba, ginsing, phenylalanine, and mixtures thereof. When the vascular dilator is ginsing it is preferable to administer from about 100 mg to 200 mg per day of a standardized herbal extract of ginsing that supplies approximately 4-7% ginsenosides, the active ingredients in ginsing. When the vascular dilator is phenylalanine it is preferable to administer from about 75 mg to 1500 mg of phenylalanine per day. The typical dose for phenylalanine is 200 mg administered three times per day. The preferred vascular dilator is extract of ginko biloba. Extract of ginko biloba contains as the active ingredient the vascular dilator ginkoflavone glycoside. A unit dose of ginko biloba is typically about 5 mg to 300 mg, preferably about 20 mg to 200 mg, and more preferably about 40 mg to 160 mg. The most preferred form of the vascular dilator is two tablets per day each containing about 60 mg of ginko biloba extract. A sufficient amount of vascular dilator can readily be determined by one of ordinary skill in the art.
xe2x80x9cFat burnersxe2x80x9d are compounds that reduce absorption of fat in the digestive tract, preferably also the digestion of fat and prevents or inhibits the production of fat. Any suitable compound that reduces absorption, or digestion of fat in the digestive tract, or prevents or inhibits the production of fat may be used. Preferred xe2x80x9cfat burnersxe2x80x9d include hydroxy citric acid and chitin. Hydroxy citric acid is believed to prevent or inhibit carbohydrates from being converted into fat. A unit dose of hydroxy citric acid is up to about 3000 mg, preferably from about 500 mg to 2500 mg, more preferably from about 750 mg to 1500 mg. The preferred source of hydroxy citric acid is extract of garcinia cambogia. Thus, when a xe2x80x9cfat burnerxe2x80x9d is included in the compositions or methods of the invention, it is preferred to administer about 1500 mg to 3000 mg of extract of garcinia cambogia, which typically contains about 50 percent hydroxy citric acid. Chitin interferes with the absorption of fat in the intestinal tract by binding with fat molecules to form large masses that the body cannot absorb and are excreted. Chitin can be administered in any amount, but it is typically administered in an amount from about 1000 mg to 2000 mg. A sufficient amount of fat burner can readily be determined by one of ordinary skill in the art.
Optionally, the composition further includes chromium picolinate. Chromium picolinate facilitates entry of sugar into cells and thus enhances the body""s ability to utilize nutrients and its own energy resources. The more efficient utilization of energy resources includes more efficient metabolism of fats by the body. A typical unit dose for chromium picolinate, when included, is from about 10 mg to 500 mg, preferably from about 100 mg to 350 mg, and more preferably from about 150 mg to 250 mg.
Compositions and methods of the invention intended for topical application may optionally include an acidic component including one or more mono- or poly-hydroxy acids, a mixture thereof, or a pharmaceutically acceptable salt or ester thereof. One of ordinary skill in the art will be readily able to select and prepare suitable mono- or poly-hydroxy acids for use in the compositions and methods of the invention, for example, alkyl hydroxycarboxylic acids, aralkyl and aryl hydroxycarboxylic acids, polyhydroxy-carboxylic acids, and hydroxy-polycarboxylic acids. Exemplary mono- or poly-hydroxy acids include: 2-hydroxyacetic acid (glycolic acid); 2-hydroxypropanoic acid (lactic acid); 2-methyl 2-hydroxypropanoic acid; 2-hydroxybutanoic acid; phenyl 2-hydroxyacetic acid; phenyl 2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyacetic acid; 2,3-dihydroxypropanoic acid; 2,3,4-trihydroxybutanoic acid; 2,3,4,5,6-pentahydroxyhexanoic acid; 2-hydroxydodecanoic acid; 2,3,4,5-tetrahydroxypentanoic acid; 2,3,4,5,6,7-hexahydroxyheptanoic acid; diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid; 4-chloromandelic acid; 3-hydroxybutanoic acid; 4-hydroxybutanoic acid; 2-hydroxyhexanoic acid; 5-hydroxydodecanoic acid; 12-hydroxydodecanoic acid; 10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid; 2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid; 3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3-methoxymandelic acid; 2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxyphenyl) lactic acid; 3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid; 3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid; 5-hydroxydecanoic acid; aleuritic acid; 2-hydroxypropanedioic acid; 2-hydroxybutanedioic acid; erythraric acid; threaric acid; arabiraric acid; ribaric acid; xylaric acid; lyxaric acid; glucaric acid; galactaric acid; mannaric acid; gularic acid; allaric acid; altraric acid; idaric acid; talaric acid; 2-hydroxy-2-methylbutanedioic acid; citric acid; isocitric acid; agaricic acid; quinic acid; glucoronic acid; glucoronolactone; galactoronic acid; galactoronolactone; uronic acids; uronolactones; ascorbic acid; dihydroascorbic acid; dihydroxytartaric acid; tropic acid; ribonolactone; gluconolactone; galactonolactone; gulonolactone; mannonolactone; citramalic acid; pyruvic acid; hydroxypyruvic acid; hydroxypyruvic acid phosphate and esters thereof; methyl pyruvate; ethyl pyruvate; propyl pyruvate; isopropyl pyruvate; phenyl pyruvic acid and esters thereof; methyl phenyl pyruvate, ethyl phenyl pyruvate, and propyl phenyl pyruvate; formyl formic acid and esters thereof; methyl formyl formate, ethyl formyl formate, and propyl formyl formate; benzoyl formic acid and esters thereof; methyl benzoyl formate, ethyl benzoyl formate, and propyl benzoyl formate; 4-hydroxybenzoyl formic acid and esters thereof; 4-hydroxyphenyl pyruvic acid and esters thereof; 2-hydroxyphenyl pyruvic acid and esters thereof; and mixtures thereof. The hydroxy acids are preferably selected from one or more alpha-hydroxy acids or beta-hydroxy acids, more preferably from glycolic, lactic, citric, tannic, or salicylic acid, and most preferably from citric or salicylic acids. It should be understood that one or more derivatives of the above acidic component, such as esters or lactones thereof, are also suitably used. One of ordinary skill in the art will also understand that various hydroxy acids described in U.S. Pat. No. 5,547,988 and 5,422,370, which are incorporated herein by express reference thereto, are also suitable for use in the compositions and methods of the invention. The acidic component is administered topically in conjunction with the compositions and methods in an amount sufficient to exfoliate, i.e., remove dead or dying skin cells, from at least a portion of the skin. The acidic component, when used, is typically present in an amount from about 0.1 to 12 weight percent, preferably from about 1 to 11 weight percent, more preferably from about 4 to 10 weight percent of the composition. For example, the acidic component may be from about 0.1 to 3 weight percent citric acid in combination with up to about 2 weight percent salicylic acid.
The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d means that amount of active ingredient(s), e.g., in a pharmaceutical composition, that provides a therapeutic benefit in the reduction or elimination of the appearance of cellulite or in the treatment, prevention, or management of one or more skin conditions.
The magnitude of a prophylactic or therapeutic dose of the composition in the management of cellulite will vary with the severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose range, for the conditions described herein, is from about 10 mg to about 20,000 mg administered in single or divided doses orally, topically, transdermally, or locally by inhalation. For example, a typical oral daily dose range should be from about 10 mg to 20,000 mg, preferably about 2,000 mg to 16,000 mg, and more preferably about 6,000 mg to 10,000 mg of the active components (i.e., excluding excipients and carriers).
It is further recommended that children, patients aged over 65 years, and those with impaired renal or hepatic function initially receive low doses, and that they then be titrated based on individual response(s) or blood level(s). It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those of ordinary skill in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
The term xe2x80x9cunit dosexe2x80x9d is meant to describe a single dose, although a unit dose may be divided, if desired. About 1 to 10 unit doses of the present invention are typically administered per day, preferably about 2 to 6 doses per day, and more preferably about 4 doses per day.
Although any suitable route of administration may be employed for providing the patient with an effective dosage of the composition according to the methods of the present invention, preferred routes include, for example, oral, rectal, parenteral, intravenous, topical, transdermal, subcutaneous, intramuscular, and like forms of administration may be employed. More preferred routes include oral or topical administration. Suitable dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, suppositories, and the like, although oral and topical dosage forms are preferred.
The pharmaceutical compositions used in the methods of the present invention include the active ingredients described above, and may also contain pharmaceutically acceptable carriers, excipients and the like, and optionally, other therapeutic ingredients. The active ingredients used in the methods and compositions can be administered individually, as a single composition that contains all the ingredients, or in any combination thereof.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic. Examples of such inorganic bases, for potential salt formation with the sulfate or phosphate compounds of the invention, include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Appropriate organic bases maybe selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (Nmethylglucamine), and procaine.
The compositions for use in the methods of the present invention may be prepared in various formulations, such as suspensions, solutions and elixirs; aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations (such as powders, capsules, and tablets), with the oral solid preparations being preferred over the oral liquid preparations. The most preferred oral solid preparations are tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
Pharmaceutical compositions for use in the methods of the present invention may be presented as discrete units such as capsules, cachets, tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder, stick, or granules, as creams (e.g., a conditioner), pastes, gels, lotions, syrups, ointments, sponges or cotton applicators, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the carrier with the active ingredient which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
For example, a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each unit dose, i.e., tablet, cachet or capsule, contains from about 1 mg to 2,000 mg of the active ingredient, preferably about 200 mg to 1,600 mg, and more preferably about 600 mg to 1,000 mg of the composition.
The compounds for use in the methods of the present invention may also be administered topically. Topical administration advantageously helps thicken the epidermis. Because of its ease of administration, a cream, lotion, or ointment represents the most advantageous topical dosage form, in which case liquid pharmaceutical carriers may be employed in the composition. These creams, lotions, or ointments, may be prepared as rinse-off or leave-on products. Each of these forms is well understood by those of ordinary skill in the art, such that dosages may be easily prepared to incorporate the pharmaceutical composition of the invention.
In addition to the common dosage forms set out above, the compounds of the invention can also be administered by controlled-release means or delivery devices that are well known to those of ordinary skill in the art, such as those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, the disclosures of which are incorporated herein by reference. Preferred controlled-release means are disclosed by: U.S. Pat. Nos. 5,427,798 and 5,486,362; WO 9404138; CA 1239034; and European Patent Application Nos. 467488 and 171457, all of which are incorporated herein by reference. These dosage forms can be used to provide slow or controlled-release of one or more of the active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the present invention.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus can affect the occurrence of side effects.
Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The term xe2x80x9ccontrolled-release componentxe2x80x9d in the context of the present invention is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient.